Breast cancer (BC) is the most common cancer in women worldwide. One in eight women will develop the disease in her lifetime. Notwithstanding the incredible progress made in this field, BC still ...represents the second most common cause of cancer-related death in women. Targeted drugs have revolutionised breast cancer treatment and improved the prognosis as well as the life expectancy of millions of women. However, the phenomenon of primary and secondary pharmacological resistance is becoming increasingly evident, limiting the efficacy of these agents and calling for a better in-depth knowledge and understanding of the biology as well as the biochemical crosstalk underlying the disease. The advent of laboratory technologies in the clinical setting such as the routine use of next generation sequencing has allowed identification of new genetic alterations as well as providing a precise picture of the molecular landscapes of each tumour. Consequently, new specific therapeutic approaches are becoming available to minimise or delay the occurrence of resistance. In this review, we analyse the latest research and news from the clinical development side for each BC subtype.
A key tool for monitoring breast cancer patients under neoadjuvant treatment is the identification of reliable predictive markers. Ki67 has been identified as a prognostic and predictive marker in ...ER-positive breast cancer. Ninety ER-positive, HER2 negative locally advanced breast cancer patients received letrozole (2.5 mg daily) and cyclophosphamide (50 mg daily) with/without Sorafenib (400 mg/bid daily) for 6 months before undergoing surgery. Ki67 expression and tumor size measured with caliber were determined at baseline, after 30 days of treatment and at the end of treatment. Patients were assigned to a clinical response category according to Response Evaluation Criteria in Solid Tumors, both at 30 days and before surgery and further classified as high-responder and low-responder according to the median variation of Ki67 values between biopsy and 30 days and between biopsy and surgery time. The predictive role of Ki67 and its changes with regard to clinical response and survival was analyzed. No differences in terms of survival outcomes emerged between the arms of treatment, while we observed a higher percentage of women with progression or stable disease in arm with the combination containing Sorafenib (20.5% vs 7.1%, p = 0.06). Clinical complete responders experienced a greater overall variation in Ki67 when compared with partial responders and patients with progressive/stable disease (66.7% vs 30.7%, p = 0.009). High responders showed a better outcome than low responders in terms of both disease-free survival (p = 0.009) and overall survival (p = 0.002). ΔKi67 score evaluated between basal and residual tumor at definitive surgery showed to be highly predictive of clinical complete response, and a potential parameter to be used for predicting disease-free survival and overall survival in luminal breast cancer treated with neoadjuvant endocrine-based therapy.
Malignant pleural mesothelioma (MPM) is a rare and aggressive form of tumour. Some mesotheliomas have been proven to be highly immunogenic. Here, we investigated the correlation between tumour ...infiltrating lymphocytes (TILs) or programmed cell death ligand 1 (PD-L1) expression with overall survival (OS) in patients with MPM. 62 Paraffin-embedded formalin fixed (PEFF) samples were analysed for TILs and PD-L1 expression. Patients were divided in 4 groups according to a cut-off of the percentage of TILs found per sample as measured by immunohistichemistry: “0” or absent (between 0 and 5%), “1” or low (between 6 and 25%), “2” or moderate (between 26 and 50%) and “3” or high (between 51 and 75%). OS was then correlated with different TILs’ expression patterns. Moreover, PD-L1 expression was assessed within the tumour as well as in the adjacent stroma on the same samples. Higher expression of peritumoral TILs (Group 2 + 3) versus Group 0 and 1 correlated with improved OS (p-value = 0.02). On the contrary PD-L1 expression seemed to be inversely correlated with clinical outcomes, even in the absence of statistical significance (HR 1.76; p = 0.083 95% IC 0.92–3.36 in areas within the tumour; HR 1.60; p = 0.176 95%; IC 0.80–3.19 in areas within the stroma). No relationship between TILs and PD-L1 expression was identified. Our research supports the use of TILs and PD-L1 expression as potential outcome predictors in patients with MPM. The use of TILs and PD-L1 as biomarkers for checkpoint inhibitors’ efficacy warrants future investigation.
Breast cancer (BC) is the second most common cause of cancer‐related deaths in women worldwide. The availability of reliable biomarkers of response/resistance to cancer treatments would benefit ...patients and clinicians allowing for a better selection of BC patients most likely to respond to a specific treatment. Phosphatidylinositol 3‐kinase (PI3K) enzymes are involved in numerous cellular‐ functions and processes. The gene encoding for PI3K catalytic subunit p110α is mutated in 20‐40% of BC. We performed a meta‐analysis of the current literature on randomized clinical trials, investigating the role of PIK3CA mutational status as prognostic factor, and predictor of response to anti‐cancer treatments. Overall 1929 cases were included. The pooled analysis confirmed that the presence of a PIK3CA mutation represents an independent negative prognostic factor (HR = 1.67, 95%CI: 1.15‐2.43; P = 0.007) in BC, as previously reported. As PI3K signaling is also a result of other pathways’ hyperactivation, further investigation of potential biomarkers able to predict likelihood of response to anti‐PI3K/mTOR, anti‐HER2, and other TKRs is warranted in future randomized clinical trials.
Breast cancer is the second most common cause of cancer‐related deaths in women. More accurate biomarkers of response to treatment and predictors of prognosis are needed. Phosphatidylinositol 3‐kinase gene is mutated in 20‐40% of BC. In our meta‐analysis PI3K is an independent negative prognostic factor and correlates with a worse prognosis (P = 0.007)
In this meta‐analysis investigating the role of PIK3CA mutations in 1928 breast cancer cases, it was proved that the mutational status of this gene was an independent negative prognostic factor, and correlated with a worse prognosis (HR = 1.67, 95%CI: 1.15‐2.43; P = 0.007).
Over the last two decades, many studies have demonstrated that the insulin-like growth factor-1 (IGF-1) is involved in a number of patho-physiological processes, as well as in the development of ...different types of solid tumors, including breast cancer (BC). Preclinical and clinical data showed that IGF-1 receptor (R) is overexpressed and hyper-phosphorylated in several subtypes of BCs. The central implications of this pathway in tumor cell proliferation and metastasis make it an important therapeutic target. Moreover, the IGF-1 axis has shown strong interconnection with estrogen regulation and endocrine therapy, suggesting a possible solution to anti-estrogen resistance. IGF-1R might also interfere with other pivotal therapeutic strategies, such as anti HER2 treatments and mTOR inhibitors; several clinical trials are ongoing evaluating the role of IGF-1R inhibition in modulating resistance mechanisms to target therapies. Our aim is to offer an overview of the most recent and significant field of application of IGF-1 inhibitors and relevant therapeutic strategies, weighing their possible future impact on clinical practice.
PDF
